Applications of the stimulation of neural tissue using light

ABSTRACT

The present invention comprises systems and methods for stimulating target tissue comprising a light source; an implantable light conducting lead coupled to said light source; and an implantable light-emitter. The light source, lead and emitter are used to provide a light stimulation to a target tissue

CROSS-REFERENCE

This application is a continuation application of U.S. patentapplication Ser. No. 12/340,169, filed Dec. 19, 2008, which is acontinuation of U.S. patent application Ser. No. 11/281,210, filed Nov.15, 2005, now abandoned, which claims the benefit of U.S. ProvisionalPatent Application Ser. No. 60/628,258, filed on Nov. 15, 2004, each ofwhich applications are hereby incorporated by reference in theirentirety.

FIELD OF THE INVENTION

The present invention relates generally to methods for stimulation ofthe nervous system.

INCORPORATED BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference. In particular,the following applications, patents, and non patent references arehereby incorporated by reference for all purposes: U.S. Publication Nos.20030208245, 20040215286, 20020183817, 20040214790, 20030144709, and20030181960; U.S. Pat. Nos. 6,921,413 and 5,716,377; and H. G. Sachs, etal., “Retinal Replacement—the Development of Microelectronic RetinalProstheses—Experience with Subretinal Implants and New Aspects”,Graefe's Arch Clin Exp Ophthalmol 242 (2004) 717-723, J. A. Turner, etal., “Spinal Cord Stimulation for Patients With Failed Back SurgerySyndrome or Complex regional Pain Syndrome: A Systematic Review ofEffectiveness and Complications”, Pain 108 (2004) 137-147; A. M. Kuncel,et al., “Selection of Stimulus Parameters for Deep Brain Stimulation”,Clinical Neurophysiology 115 (2004) 2431-2441; M. Capecci MD, et al.,“Chronic Bilateral Subthalamic Deep Brain Stimulation in a Patient withHomozygous Deletion in the Parkin Gene”, Movements Disorders Vol. 9(12)(2004) 1450-1452; and K. H. Sipson, et al., “A Randomized, Double-Blind,Crossover Study of the Use of Transcutaneous Spinal Electoanalgesia inPatients with Pain from Chronic Critical Limb Ischemia” Journal of Painand Symptom Management Vol, 28(5) (2004) 511-516.

BACKGROUND

Prior art has disclosed many methods of stimulating neural tissue usingelectricity. Recently, prior art has disclosed means of directlystimulating a peripheral nerve in an experimental preparation using alaser. The present invention discloses application of methods forstimulating target tissue using light or optical energy.

As disclosed in U.S. Pat. No. 6,921,413, upon which some aspects of thisinvention expand, various methods may be used to stimulate neuraltissue. Several of the traditional methods of stimulation includeelectrical, mechanical, thermal, and chemical. A neuron will propagatean electrical impulse after applying a stimulus. The most common form ofapplying such stimulus is to form a transient current or voltage pulseapplied through electrodes. Electrical stimulation, as well asmechanical and chemical stimulation, has many limitations. To name afew, stimulation by such methods may result in nonspecific stimulationof neurons or damage to neurons. Difficulty exists in recordingelectrical activity from the neuron due to an electrical artifactcreated by the stimulus. To stimulate only one or a few neurons, fragilemicro-electrodes need to be fashioned and carefully inserted into thetissue to be stimulated. Such techniques do not easily lend themselvesto implantable electrodes used for long term stimulation of neuraltissue.

Fork was the first to report a direct stimulation of nerve fibers usinglow-energy laser light (Fork, R., “Laser stimulation of nerve cells inAplysia”, Science, March(5): p. 907-8, 1971.) According to Fork et al.,laser irradiation at (488 nm, 515 nm, and 1006 nm) was applied to theabdominal ganglion of Aplysia Californica that possesses some lightsensitive properties. The author observed that the cells fired when thelight at 488 nm was turned on in some cases and turned off in others. Inanother study, bundles of rat nervous fibers may be stimulated using aXeCl laser (Allegre, G., S. Avrillier, and D. Albe-Fessard, “Stimulationin the rat of a nerve fiber bundle by a short UV pulse from an excimerlaser”, Neuroscience Letters, 180(2): p. 261-4, 1994.) When stimulatedusing a laser pulse transmitted through an optical fiber, a responsesimilar to that obtained with electrical stimulation was observed. Athreshold stimulation level of 0.9 J/cm² was reported for opticalstimulation. No other reports by the same authors have been publishedsince. Thus, optical energy can be used to stimulate nerve fibers.Although there is ample evidence that photon energy effects neuraltissue in humans and animals, a need remains for a method that can beused to stimulate neural tissue without damaging such tissue orproducing artifacts. Furthermore, in order for such an invention to beuseful in both research and clinical applications, it should produceactivity in neurons by delivery of energy without the addition ofpotentially toxic dyes or at intensities destructive to the neuron overuseful periods of time. Finally, there is a need for a method ofprecisely stimulating an individual neuron with optical energy withoutpiercing tissue.

One common way of providing light energy for stimulation of neuraltissues is by using a laser. Lasers are characterized by theirwavelength and energy level. Classically, lasers have been used inbiological applications for tissue ablation. However, low power lasersare available for uses other than tissue ablation. The energy requiredfor stimulation large populations of neurons is very small, and theenergy required to stimulate an individual neuron is exceedingly small.Manipulation of strength, duration and frequency of stimulation are keyparameters that determine whether a neuron will fire. Such parametersare adjustable with pulsed, optical energy and can be adjusted to arange acceptable for stimulation of neural tissue. Additionally, theprecision of laser energy delivery can easily provide a novel method ofselectively stimulating individual neurons or different nerve fiberswithin a large population of neurons without the need to pierce tissue.

The present invention provides methods for stimulating neural tissuewith optical energy. Stimulation of neural tissue in this regardincludes, but is not limited to, generation and propagation of anelectrical impulse in one or more neurons after applying an opticalstimulus. In addition, there is a unique basic science and clinical needfor producing an artifact-free response in neurons that causes no damageto the tissue.

One advantage of the present invention is that the methods ofstimulating neural tissue described herein may be contemplated to behighly specific to individual nerve fibers or small groups of nervefibers. As intensity of electrical stimulation increases, progressivelygreater numbers of neurons are activated. This is a physical property ofassociated with increasing the electrical field size. Optical energy,however, can be confined to a predetermined, physical “spot” size, whichis independent of the energy delivered. This physical property is whatallows optical techniques to be unique in stimulation of individual orselected neurons. Another advantage of the present invention is the useof the methods of stimulation of neural tissues in vivo. In vitromethods of stimulation, on the other hand, do not lend themselves to theuses of an in vivo method.

Still another advantage of the present invention is that opticalstimulation of neural tissue is not associated with an electricalstimulus artifact. Thus, when optically stimulating individual ormultiple neurons stimulated by optical energy, electrical stimulusartifacts are not present.

Still another advantage of this method is that the use of low energylaser stimulation provides precise localization without tissue contact,resulting in high specificity. Such specificity is of use clinicallywhen nerve stimulation is used for diagnostic applications likeidentification of subsets of peripheral nerve fibers during operativerepair of severed nerves. Also, such technology would allow multiple,focused laser stimuli, to be used to provide functional mapping ofneural networks and their interconnections. This advantage may also beapplied in therapeutic situations such as neural modulation for painmanagement, control of movement disorders, and seizure reduction.

SUMMARY OF THE INVENTION

In one embodiment, the present invention involves a system forstimulating target tissue comprising: a light source for providingstimulation pulses; an implantable light conducting lead coupled to saidlight source adapted for stimulation of a predetermined site in asubject. In one aspect, the light conducting lead is an optical fiber.In another aspect the light source is a laser. In one aspect, the lightsource is implantable.

In one embodiment, the present invention relates to a method of treatinga disorder comprising: implanting at least one light-emitter coupled toa light source such that it is in communication with at least onepredetermined site in the nervous system of a body; stimulating said atleast one predetermined site in said nervous system of said body usingsaid at least one light-emitter. In one aspect of the invention, thedisorder being treating is Parkinson's disease, Alzheimer's disease,depression, or epilepsy. In one aspect of the invention, the abovemethod further includes the step of regulating at least one parameter ofsaid step of stimulating, said at least one parameter being selectedfrom the group consisting of pulse width, pulse frequency, and pulseamplitude.

In one embodiment, the present invention relates to a method fortreating a disorder in a patient comprising the steps of: surgicallyimplanting a light-emitter into a brain of a patient wherein said lightemitter is coupled to a light source and a signal generator operatingsaid light source; and operating said signal generator to stimulate apredetermined treatment site in said brain.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagrammatic illustration of an light-emitter implanted in abrain according to a preferred embodiment of the present invention and asignal generator coupled to the light-emitter;

FIG. 2 is a diagrammatic illustration of a portion of the nervous systemof the human body in which a preferred form of motion sensor, signalgenerator and light-emitter 25 have been implanted;

FIG. 3 is a schematic block diagram of a microprocessor and relatedcircuitry used in a preferred embodiment of the invention; and

FIG. 4 is a flow chart illustrating a preferred form of a microprocessorprogram for generating stimulation pulses to be administered to thebrain.

FIG. 5 is an illustration of implantation of a stimulator, and usewithin the vascular system.

FIGS. 6-8 present example target areas for stimulation, with relatedconsequences.

FIG. 9 presents an example of placement of multiple light-emitters.

FIG. 10 presents additional examples of types of light sources.

FIG. 11 presents an exemplary nerve cuff as used in the methods herein.

DETAILED DESCRIPTION OF THE INVENTION A. Definitions

Deep brain stimulation (DBS), as used herein refers to the stimulationof neural tissue using either conventional electrical stimulationmethods, or using light stimulation methods as disclosed herein.

Light, as used herein, refers to optical energy or electromagneticradiation. This optical energy may have any wavelength, includingvisible light as well of energy with longer and shorter wavelengths.This light may include laser light.

Light source, signal generator, as used herein refers to a source oflight, electromagnetic radiation or optical energy. This source may beused to produce energy in order for this energy to be conveyed to atarget tissue so that the target tissue is activated or inactivated bythe optical energy. The light source may provide for pulsatile ormodulated light to be produced. The light source may provide for shortmicropulses (eg 0.1-1000 picosecond) formed into trains within longermacropulses (eg 0.1-1000 microseconds) which in turn may be controlledin trains or other temporal patterns. The light source may be a laserlight source or other light source. The light source may be controlledby a microprocessor, computer or computer program that determines thepattern, or signal, to be presented. Any among the light source,microprocessor, power supply, biocompatible protective casing, leads,and related hardware may be implanted within the subject.

Light-emitter, as used herein, refers to a point from whichelectromagnetic radiation is given out, for example given out so that itstrikes a target tissue. A light-emitter may be used as a stimulator oftarget tissue using light. A light-emitter may stimulate a target tissueusing light or optical energy by propagating the light or optical energyinto the target tissue. For example, a light-emitter may be the end ofan optical fiber adjacent to a target tissue and through which light isconducted. An example is presented in FIG. 1, 25.

Light conductor, as used herein refers to a means to conduct light oroptical energy from one location to another, including but not limitedto an optical fiber.

Neuromoanatomical texts, as used herein refers to any of a variety oftexts describing the structures of the brain that may be used as targettissues of this invention, including but not limited to FundamentalNeuroanatomy by Nauta and Feirtag, and in the Co-Planar SteriotaxicAtlas of the Human Brain by Jean Talairach and Pierre Tournoux, MagneticResonance Imaging of the Brain and Spine (2 Volume Set) by Scott W., Md.Atlas.

Neuromodulator or neuromodulatory substance, as used herein, refers tocompounds which can alter activity or responsiveness in one or morelocalized regions of the brain. Examples of neuromodulators include, butare not limited to: opioids, neuropeptides, acetylcholine, dopamine,norepinephrine, serotonin and other biologic amines, and others. Manypharmacologic agents such as morphine, caffeine and prozac are exogenousmimics of these neuromodulatory substances.

Neuromodulatory centers, as used herein, refers to regions of the brainor nervous system that serve to regulate or alter responsiveness inother parts of the nervous system. Examples include regions that containneurons that release neuromodulatory transmitters such ascatecholamines, acetylcholine, other biologic amines, neuropeptides,serotonin, norepinephrine, dopamine, adrenaline. These centers and theactions produced through their modulation are described in neuroanatomytexts and The Biochemical Basis of Neuropharmacology, Cooper, Bloom andRoth. Examples include but are not limited to the nucleus raphe magnus,substantia nigra (pars compacta and reticulata), nucleus accumbens,periaqueductal gray, locus coeruleus, nucleus basalis, red nucleus,nucleus accumbens. These regions may serve as target tissues.

Optical fiber, as used herein, refers to a flexible substantiallyoptically transparent fiber, usually made of glass or plastic, throughwhich light can be transmitted by successive internal reflections. Inaddition, this invention discloses that other means for conveying lightfrom a source to a precise spatial location may be used in place of anoptical fiber.

Pharmacological treatment, as used herein, refers to the administrationof any type of drug or medication.

Region of interest or ROI or volume of interest, as used herein, refersto a particular one or more voxels of the body, nervous system or brainof a subject. An ROI may occasionally be referred to as an area orvolume of interest since the region of interest may be two dimensional(area) or three dimensional (volume). Frequently, it is an object of themethods of the present invention to monitor, control and/or alter brainactivity in the region of interest. For example, the one or regions ofinterest of the brain associated with a given condition may beidentified as the region of interest for that condition. In onevariation, the regions of interest targeted by this invention areinternal relative to a surface of the brain.

Reward centers or pleasure centers, as used herein, refers to areas ofthe brain which, when active, produce pleasurable or rewardingexperiences or sensations. These include, but are not limited to certainlimbic structures, the nucleus accumbens, locus coeruleus, septalnuclei, and others. These may also include areas that have beenassociated with addictive behaviors. These may serve as target tissues.

Single point, as used herein, refers to an individual geometric locus orsmall area of volume, such as a single small geometric volume from whicha physiological measurement will be made, with the volume being 0.01, 1,0.5, 1, 2, 3, 4, 5, 10, 15, 20, 30, 50, 100 mm in diameter. A devicemaking a measurement from a single point is contrasted with a devicemaking scanned measurements from an entire volume comprised of manysingle points.

Spatial array, as used herein, refers to a contiguous or non-contiguousset of single points, areas or volumes in space. The spatial array maybe two dimensional in which case elements of the array are areas orthree dimensional in which case elements of the array are volumes.

Spatial pattern, or spatial activity pattern, or vectorized spatialpattern, as used herein, refers to the activities of a set of singlepoints forming a two dimensional or three dimensional spatial array. Avector comprising a value for each point in a three dimensional spatialarray is one example of a spatial pattern, or a value for each point ateach moment in time is another example of a spatial pattern.

Subject, as used herein, refers to a target whose activity is to becontrolled in conjunction with performing the methods of the presentinvention. It is noted that the subject may be the person who has thecondition being treated by the methods of the present invention.Subjects may also refer to animal subjects, or to target tissue takenfrom animals or humans.

Tissue or target tissue, as used herein, refers to biological tissues towhich this invention may be applied. These tissues include, but are notlimited to, excitable tissue, tissue in either the central nervoussystem, peripheral or cranial nerves, autonomic nervous tissue, smoothor striated muscle tissue, vascular tissue. These target tissues may bein humans or animals. These target tissues may be either in the in vivosetting (ie inside the subject) or may have been removed from thesubject (eg for use in isolated tissue from the nervous system such asfor study of a hippocampal or other slice preparation).

Referring to FIG. 1, a system or device 10 made in accordance with apreferred embodiment may be implanted below the skin of a patient. Alead 22A is positioned to stimulate a specific site in a brain (B). Thisstimulation may include stimulation of neuronal activity. Device 10 maytake the form of a modified signal generator. Lead 22A may take the formof a light conductor, including an optical fiber, for stimulating thebrain, and is coupled to device 10 by a light conductor 22.

The distal end of lead 22A terminates in one or more stimulationlight-emitters 25 generally designated a stimulator group 115 implantedinto a portion of the nervous system, for example by conventionalstereotactic surgical techniques. However, other numbers oflight-emitters 25, such as 2, 3, 4, 5, 6-10, 10-20, 20-30, 30-50,50-100, 100-200, 200-1000, 1000-5000, or 5000-10000 may be used forvarious applications or in some embodiments more than 2, 3, 4, 5, 6, 7,8, 9, or 10 light-emitters can be used. Each of the light-emitters 25 isindividually connected to device 10 through lead 22A and light conductor22. Lead 22A may be surgically implanted through a hole in the skull 123and light conductor 22 is implanted between the skull and the scalp 125as shown in FIG. 1. In this regard, a lead may be an apparatus forconveying light, including one or more optical fibers. Light conductor22 is joined to implanted device 10 in the manner shown. Referring toFIG. 2, device 10 is implanted in a human body 120 in the locationshown. Body 120 includes arms 122 and 123. Alternatively, device 10 maybe implanted in the abdomen, and emitters 25 may be placed adjacent toperipheral or cranial nerves 131, or in or near striated or smoothmuscle.

Light conductor 22 may be divided into twin leads 22A and 22B that areimplanted bilaterally as shown. Alternatively, lead 22B may be suppliedwith stimulating pulses from a separate conductor and signal generator.Leads 22A and 22B could be 1) two light-emitters 25 in two separatenuclei that potentiate each others effects or 2) nuclei with oppositeeffects with the stimulation being used to fine tune the responsethrough opposing forces.

The light emitters 25 may be positioned by viewing tissue internal tothe subject using a laparascopic or other camera connected to a viewingdevice 32 placed near to the light emitters. In addition, the lightconductor 22, since it may conduct light in both directions, may be usedalternately for viewing the internal structure of the subject, andsubsequently for light stimulation. In addition, fluid, gas,substantially light transparent media 35, or other agents includingdrugs or pharmacological agents may be passed into the subject through acatheter 34 near to the light emitter, stimulator.

A sensor 130 is attached to or implanted into a portion of a patient'sbody suitable for detecting symptoms of a disorder being treated, suchas a motor response or motor behavior. Sensor 130 is adapted to sense anattribute of the symptom to be controlled or an important relatedsymptom. For motion disorders that result in abnormal movement of anarm, such as arm 122, sensor 130 may be a motion detector implanted inarm 122 as shown. For example, sensor 130 may sense three-dimensional ortwo-dimensional motion (linear rotational or joint motion), such as byan accelerometer. One such sensor suitable for use with the presentinvention is described in U.S. Pat. No. 5,293,879 (Vonk). Anothersuitable accelerometer is found in pacemakers manufactured by Medtronic,Inc. and described in patent application Ser. No. 08/399,072 filed Mar.8, 1995, in the names of James Sikorski and Larry R. Larson and entitled“Package Integrated Accelerometer”. Sensor 130 also may be placed indevice 10 in order to detect abnormal movement resulting from the motiondisorder being treated.

Sensor 130 also may be capable of detecting gravity direction or motionrelative to some object (e.g., a magnet) either implanted or fixednearby. Sensor 130 also may take the form of a device capable ofdetecting force in muscles or at joints, or pressure.

Sensor 130 may detect muscle EMG in one, two or more muscles, or inreciprocal muscles at one joint. For such detection, sensor 130 may takethe form of a recording electrode inserted into the muscle of interest.

Brain neurophysiological signals including single neuron recordings orEEG (e.g., motor cortex potentials recorded above the motor neuronscontrolling specific muscle groups) also may be detected by sensor 130.

Yet another form of sensor 130 would include a device capable ofdetecting nerve compound action potentials (e.g., either sensoryafferent information from muscle or skin receptors or efferent motorpotentials controlling a muscle of interest).

For certain types of patients, sensor 130 may take the form of devicedetecting the posture of the patient.

-   Sensor 130 also may take the form of a device capable of detecting    nerve cell or axon activity that is related to the pathways at the    cause of the symptom, or that reflects sensations which are elicited    by the symptom. Such a sensor may be located deep in the brain. For    such detecting, sensor 130 may take the form of an electrode    inserted into the brain. Signals that are received by the sensor may    by amplified before transmission to circuitry contained within    device 10.

Sensor 130 may take the form of a transducer consisting of an electrodewith an ion selective coating applied which is capable of directlytransducing the amount of a particular transmitter substance or itsbreakdown by-products found in the interstitial space of a region of thebrain such as the ventral lateral thalamus. The level of theinterstitial transmitter substance is an indicator of the relativeactivity of the brain region. An example of this type of transducer isdescribed in the paper “Multichannel semiconductor-based electrodes forin vivo electrochemical and electrophysiological studies in rat CNS” byCraig G. van Home, Spencer Bement, Barry J. Hoffer, and Greg A.Gerhardt, published in Neuroscience Letters, 120 (1990) 249-252.

For tremor, the relative motion of a joint or limb or muscle EMG may beproductively sensed. Sensing electrical activity of neurons in variouslocations of the motor circuitry also is helpful. Recording theelectrical activity in the thalamus or cerebellum will reveal acharacteristic oscillating electrical activity when tremor is present.

For Ballism, Hemiballism or tremor, sensor 130 may take the form of anaccelerometer detecting relative motion of a joint and limb or muscleEMG.

For Dystonia, sensor 130 may take the form of a device for detectingrelative motion of a joint or limb or muscle EMG.

Referring to FIGS. 2 and 3, the output of sensor 130 is coupled by cable132, comprising conductors 134 and 135, to the input of an analog todigital converter 206 within device 10. Alternatively, the output of anexternal sensor would communicate with the implanted pulse generatorthrough a telemetry downlink.

It may be desirable to reduce parameter values to the minimum levelneeded to establish the appropriate level activity in a target region.In FIG. 4, steps 410 through 415 constitute the method to adjuststimulation parameters using a feedback mechanism that detects a resultof stimulation. When parameters are changed, a timer is reset in step415. If there is no need to change any stimulus parameters before thetimer has counted out, then it may be possible due to changes inactivity to reduce the parameter values and still maintain appropriatelevels of activity in the target, or in downstream processes effected bythe target. At the end of the programmed time interval, device 10 triesreducing a parameter in step 413 to determine if control is maintained.If it is, the various parameter values will be ratcheted down until suchtime as the sensor values again indicate a need to increase them. Whilethe algorithms in FIG. 4 follow the order of parameter selectionindicated, other sequences may be programmed by the clinician.

Microprocessor 200 within device 10 can be programmed so that thedesired stimulation can be delivered to the specific brain sitesdescribed. Alternatively, sensor 130 can be used with a closed loopfeedback system in order to automatically determine the type ofstimulation necessary to alleviate motor disorder symptoms as describedin connection with FIG. 4.

Microprocessor 200 may execute an algorithm in order to providestimulation with closed loop feedback control. At the time thestimulation device 10 is implanted, the clinician may program certainkey parameters into the memory of the implanted device via telemetry.These parameters may be updated subsequently as needed. Step 400 in FIG.4 indicates the process of first choosing whether the neural activity atthe stimulation site is to be blocked or facilitated (step 400(1)) andwhether the sensor location is one for which an increase in the neuralactivity at that location is equivalent to an increase in neuralactivity at the stimulation target or vice versa (step 400(2)). Next theclinician must program the range of values for pulse width (step400(3)), amplitude (step 400(4)) and frequency (step 400(5)) whichdevice 10 may use to optimize the therapy. The clinician may also choosethe order in which the parameter changes are made (step 400(6)).Alternatively, the clinician may elect to use default values.

The algorithm for selecting parameters is different depending on whetherthe clinician has chosen to block the neural activity at the stimulationtarget or facilitate the neural activity. FIG. 4 details steps of thealgorithm to make parameter changes.

The algorithm uses the clinician programmed indication of whether theneurons at the particular location of the stimulating light-emitter 25are to be facilitated or blocked in order to reduce the neural activityin the subthalamic nucleus to decide which path of the parameterselection algorithm to follow.

It is desirable to reduce parameter values to the minimum level neededto establish the appropriate level of neuronal activity in thesubthalamic nucleus. Superimposed on the algorithm just described is anadditional algorithm to readjust all the parameter levels downward asfar as possible. In FIG. 4, steps 410 through 415 constitute the methodto do this. When parameters are changed, a timer is reset in step 415.If there is no need to change any stimulus parameters before the timerhas counted out, then it may be possible due to changes in neuronalactivity to reduce the parameter values and still maintain appropriatelevels of neuronal activity in the target neurons. At the end of theprogrammed time interval, device 10 tries reducing a parameter in step413 to determine if control is maintained. If it is, the variousparameter values will be ratcheted down until such time as the sensorvalues again indicate a need to increase them. While the algorithms inFIG. 4 follow the order of parameter selection indicated, othersequences may be programmed by the clinician.

Appropriate stimulation pulses may be generated by device 10 based onthe computer algorithm shown in FIG. 4 that read the output of converter140 and makes the appropriate analysis.

For some types of conditions, a microprocessor and analog to digitalconverter will not be necessary. The output from sensor 130 can befiltered by an appropriate electronic filter in order to provide acontrol signal for device 10.

The type of stimulation administered by device 10 to the brain dependson the specific location at which the stimulator groupl 15 of leads 22Aare surgically implanted. The appropriate stimulation for the portion ofthe basal ganglia or thalamus in which lead 22A terminates, togetherwith the effect of the stimulation on that portion of the brain forhyperkinetic motion disorders is provided.

FIG. 5 shows an example of this invention that uses an implantedcontainer 510 containing a battery 520 or other power source capable ofdriving a light source 530 that produces light and transmits it eitherdirectly to target tissue or through an optical fiber 540 to targettissue where it may optionally be focused through a lens onto a targettissue. In the example shown the target tissue is the heart 560, so thedevice is able to function as a pacemaker by activating atrial tissue.In addition, the optical fiber is passed through the lumen of a bloodvessel.

Methods are provided for applications of stimulating target tissuewherein the source of stimulation is optical energy. This inventiondiscloses applications of this basic principle, disclosed in U.S. Pat.No. 6,921,413. In certain embodiments of the method, a free electronlaser is used as a source of optical energy. It is possible to usesources other than free electron lasers that are capable of generatingthe appropriate wavelengths, pulses, and energy levels.

Implantable Light Sources

Using this invention the light source used for stimulation may beimplantable as shown in FIG. 1. Implantable light sources 10 may be usedas a replacement for electrical stimulators as they are used withelectrical stimulation for long term chronic stimulation applicationsincluding, but not limited to, heart pacing, spinal cord stimulation,deep brain stimulation, cranial or peripheral nerve stimulation, vagalnerve stimulation. For an implantable light source a battery and lightsource such as a laser may be placed inside a biocompatible protectivecontainer with the light source. The light source may be a diode laser.Methods for implantable manufacture of batteries and light sources maybe provided, for example, as described in U.S. Pat. No.6,925,328—MRI-Compatible Implantable Device. In the currently disclosedinvention, unlike in U.S. Pat. No. 6,925,328, light may be used fordirect stimulation of target tissue, rather than light being convertedinto an electrical signal which is then used to stimulate tissue.

Implantable Leads

Leads 22 for use in this invention may comprise light conductors asshown in FIG. 1. Leads for use in this invention may be optical fibers.Leads for use in this invention may be fiber optic bundles. Inelectrical stimulation methods disclosed previously, leads are typicallyelectrical wires. Here, it is disclosed that implantable electricalleads may be replaced by leads that convey light in order to directlystimulate target tissue with light. In one embodiment, fiber optic leadsused in this invention may be implantable and biocompatible. In anotherembodiment, the leads may be percutaneous, connecting a light source orlaser outside of the body with a stimulus location inside the body.Methods and apparatus for percutaneous passage of lead wires used inelectrical stimulation may be used for percutaneous passage of lightconductors.

Implantable Light-Emitters

In one embodiment, light-emitters 25 used in this invention may beimplantable and biocompatible as shown in FIG. 1. This may haveadvantages over electrical stimulation electrodes in that electricalstimulation may lead to tissue necrosis or electrolytic reactions notpresent with light stimulation. Light-emitters 25 may include either thebare end of a fiber optic, may include a biocompatible lens, and mayinclude a biocompatible window 23 through which light is presented.

Window

Stimulation may be applied through a window 23 that serves to form aseal as shown in FIG. 1. This may allow stimulation minimizing risk ofinfection. The window 23 may be composed of material that issubstantially transparent to the stimulating energy. The window 23 maybe coated so as to prevent adhesion of biological materials or otherobstructions to the light path. This window 23 may be held in placethrough an appliance that secures it to the skin, to bone, or toconnective tissue. This may allow for light stimulation to regionsinternal to a subject while maintaining intact bodily boundaries of thesubject.

Conducting Medium, Laparoscopy

In addition, methods may be used to provide a conducting medium betweenthe light-emitter 25 and the target tissue, which may be passed throughcatheter 34 as shown in FIG. 1. This conducting medium may comprisewater, a solution substantially transparent to the stimulating energy,or gas. In one embodiment, a method may be provided to convey a gas ortransparent solution into the body in order to displace internal organsor fluids so that stimulation using light may take place unobstructed byother internal organs or fluids. For example, a catheter placedalongside the light conductor may be used to pass a transparent fluidinto the body of the subject. In this way, the internal aspects of thebody of the subject may be visualized through a light conductor, forexample using a laparascope. In addition, if a substantially transparentfluid or gas 35 is passed into the body, this may be used to allow lightto pass from the light emitter to the target tissue. This transparentfluid may displace less transparent organs or bodily fluids of thesubject. Aspects of the invention provided here may be completed inconjunction with conventional laparoscopic methods, for example asdiscussed in Cuschieri A. “Laparoscopic surgery: current status, issuesand future developments.” Surgeon. 2005 June 3(3):125-30, 132-3, 135-8.For example, light stimulation of target tissues may be performed usinglaparascopic placement of one or more light emitter, and visualizationthrough light conductor 32.

Nerve Inactivation (as Opposed to Stimulation)

The disclosed device may be used for target inactivation. For example,using high frequency pulses may be used to inactivate neural tissue. Thefrequency may be 100-1000 Hz, 1000-5000 Hz, 5-10 kHz, 10-20 kHz, 20-50kHz, 50-500 kHz or greater. Through applying a long (>1s) train ofrepetitive light pulses, a target tissue may become fatigued,habituated, or otherwise inactivated.

Monitoring of Activation Induced Using Neuroimaging, Fmri, Real TimeFmri

Activation resultant from stimulation using this device may be used incombination with any method for measuring biological tissue activation.In one embodiment, this invention provides for a nerve conduction studyto be made in a subject through stimulating a nerve using light, andrecording the resultant activation using recording electrodes followingmethods common in the art but previously using electrical stimulation ofthe nerve. This method may be used for nerve conduction studies inhumans. This method provides for nerve conduction studies using any ofthe peripheral or cranial nerves. In addition, this device may be usedin conjunction with fMRI as a measure of neural activation, or real timefMRI.

Intravascular Implantation

In one embodiment, a light-emitter and lead may be implantedintravascularly, as shown in FIG. 5. This implantation may use a directadaptation of methods familiar to one skilled in the art for theintravascular implantation of wire leads, substituting or adding a fiberoptic lead and light-emitter to a wire lead. In one embodiment,stimulation may be of target tissue inside the vascular system, such asheart muscle tissue or other vascular tissue. In another embodimentstimulation may take place across the vascular wall, using light tostimulate target tissue beyond the vascular wall. In another embodimentthe vascular system may be used as a conduit to place a light-emitterand lead, which then exit the vascular system through a vascular wall inorder to stimulate target tissue outside of the vascular system.

Light Sources and Parameters

This invention may employ any form of radiant energy sufficient tostimulate activity in target tissues.

In one embodiment, a free electron laser and delivery optics may be usedto generate and manipulate the light, or optical energy. The opticalenergy transport system may be maintained under rough vacuum. Theoptical energy may be focused on the target neural tissue using focusinglenses (for example Vi Convex Lenses, f=300 mm) to a spot size of forexample 400 micrometers. Optical stimulation may be performed usinglaser pulses with energy in the range from 0.2 mJ to 5 mJ with a spotsize of 300-600 micrometers (fluence values varied from 0.2 J/cm² toabout 10 J/cm²). The minimum energy and therefore fluence required tostimulate a frog nerve preparation as described in U.S. Pat. No.6,921,413 may be minimum (0.6 J/cm.²) between 4 and 4.5 micrometers. Thelaser pulses may be focused onto the sciatic nerve using BiconvexLenses. The laser pulse energy may be varied using a polarizer.

The FEL may offer the flexibility of providing various wavelengths inthe infrared spectrum for use with the method provided herein. Othersources may be used to generate the necessary wavelength. In addition toany source that can generate wavelengths in the infrared portion of thespectrum, sources may include LED and LCD. FEL additionally may providemicropulses, each about 1 picosecond in duration and having a repetitionrate of about 3 GHz. The envelope of this pulse train may formsmacropulse that is about 3-6 microseconds and may be delivered at a rateup to 30 Hz or higher. As mentioned above, optical stimulation of theperipheral nerves may employ pulse energies ranging from 0.2 mJ to 5 mJin a spot size of around 500 micrometers.

Stimulation studies can also be performed using other sources such as aYAG laser for wavelengths in the UV, visible and infrared. Additionally,if it is desired to use a wavelength around 4 micrometers, then alead-salt laser, or an optical parametric oscillator (or amplifier) maybe used.

Various light wavelengths from 2 micrometers to 6.45 micrometers may beused to stimulate neural tissue. FEL wavelength of 6.45 micrometers maybe effective, possibly due to the amid II vibrational band of protein(Edwards, et al., Nature, 371(6496): 416-419, 1994). While using thewavelength of 6.45 micrometers, nerve stimulation may occur at a pulseenergy of 4.5-5.0 mJ/pulse, with a spot size measured of close to 0.5mm.

Optical energy without a wavelength around the water absorption peak, at2.94 micrometers, may be used for optical stimulation. In addition,using wavelengths of 3.1 micrometers and 3.3 micrometers may provide anerve response however, these wavelengths may have a greater potentialfor causing damage to the neural tissues.

By using wavelengths in the range from 3.8 micrometers to 5.5micrometers, a valley for the water absorption, the effects ofphoto-ablation may be minimized. Wavelengths around 4 micrometers may bemore efficient in eliciting nerve response compared to other testedwavelengths.

Since FEL emits continuous laser pulses, an electromechanical shuttermay be used to select a single pulse from the pulse train. Melles Griot(Irvin, Calif.) electronic shutter is used for gating laser pulses toobtain a single pulse from the pulse train. The shutter controller maybe triggered using the trigger pulse from the laser.

Optical energy may be focused in a spatial area in the range of 1-5,5-10, 10-20, 20-50, 50-100, 100-200, 200-500, 500-1000, 1000-5000,5000-10000, 10000-100000 micrometers. Also, the target neural tissue mayreceive the optical energy for an amount of time necessary to provide astimulation effect. The optical source may be pulsed. In one embodimenteach energy pulse may be in a range of from 1 picosecond to 10picoseconds micropulse and from 1 to 10 microsecond macropulse. Thewavelength used is a wavelength that may approximately correspond to avalley for water absorption of a neural tissue. Such valleys of waterabsorption may be in the wavelength ranges of 0.9 micrometers to 2.7micrometers and 3.8 micrometers to 5.5 micrometers. Additionally, thewavelength used may be approximately 4.5 micrometers, approximately 2.2micrometers, or approximately 1.23 micrometers. In other embodiments,the wavelength may be 4.4 micrometers, the energy output may be 1.5 mJ,the optical energy may occur in an area of 600 micrometers. In otherembodiments micropulses may be in the range of: 0.1-1, 1-10, 10-100,100-1,000, 1,000-10,000, 10,000-100,000 picoseconds or less than 1, 0.5,0.1, 0.05, 0.01, 0.005, 0.001, or 0.0005 microseconds. Macropulses maybe in the range of: 1-10, 10-100, 100-1,000, 1,000-10,000,10,000-100,000 microseconds or greater than 1, 5, 10, 50, 100, 500,10,000, 50,000 or 100,000 microseconds.

In addition to these parameters, this invention provides for thepossibility of adjusting the light source, light delivery method,wavelength, pulse width, pulse amplitude, and pulse duration ofstimulating light to produce activity, and then using the selectedprarameters for further stimulation as provided here. In addition, asfurther research into light stimulation produces optimized lightsources, light delivery methods and parameter sets, these may be used inconjunction with this invention.

Hardware

A group of multiple light emitters 115 may be individually controlled topass through separate light conductors 22, with each light conductorpositioned at a different target location. In this way, bydifferentially applying light through each light conductor, spatialpatterns of activation may be presented that activate differentcombinations of locations of neural tissue. In addition, thismulti-channel stimulation configuration, as shown in FIG. 1, may becomputer controlled using a computer within device 10 so that spatialpatterns may be created. This may be completed using optical switchingtechnologies within device 10. The computer controller may select whichlight conductors receive light pulses, and the exact times, durations,and intensities of stimulation. In this way, complex spatio-temporalpatterns of stimulation may be produced on the target neural tissue.This may also be seen in FIG. 9. This allows different neural elementsto be stimulated in arbitrary patterns in space and time.

The following components may be used in combination with this invention:free space beam, grin lens, tunable laser, solid state laser tunable byinterferometer changes the length of the cavity, chemical lasers.

Stimulation Parameters

In electrodes, ‘electrical targeting’ can be used to control neuralactivation by controlling the spread of the electric field and byselectively activating neural elements (Kuncell, et. al. 2004).Similarly, using light stimulation it is possible to select thestimulation parameters used to specify what neural elements will bestimulated.

Along with accurately placed electrodes, successful DBS depends onproperly set stimulus parameters, including pulse width, frequency, andamplitude (Su et al., 2003). Typical DBS parameter settings usingelectrical stimulation may include voltage, pulse width, and frequencyrange from 1-3.5 V, 60-210 ms, and from 130-185 Hz (Moro et al., 2002;O'Suilleabhain et al., 2003; Rizzone et al., 2001; Volkmann et al.,2002). In a study comparing the efficacy of GPi and STN DBS, the finalmean stimulus parameter settings used to treat PD symptoms were 3 V, 82ms, and 152 Hz for STN DBS, and 3.2 V, 125 ms, and 162 Hz for GPi DBS(Obeso et al., 2001). Similarly, pulse width, frequency, and amplitudemust be accurately selected for light stimulation of neural tissue.Light stimulation durations and frequencies may be based upon thosefound successful in electrical stimulation. Light stimulus parametersmay be used to control selectively which neural elements in thesurrounding tissue are excited. The stimulus parameters may also controlthe spatial extent of neural elements which are excited.

Stimulation frequencies using light stimulation may be substantiallysimilar to those using electrical stimulation. Pulse widths may besubstantially shorter.

In order to select the appropriate pulse width and amplitude, each ofthese two parameters may be varied independently while the stimulationresponse is measured in order to determine the optimal combination ofpulse width and amplitude that just produces a change in activity in thetarget tissue while depositing a minimum amount of energy, or elicitingminimum tissue damage. Then, this pulse width and amplitude combinationmay be used at a repetition frequency appropriate to stimulate orinhibit the activity of the target region. The optimal combination maybest reduce symptoms, minimize side effects, and minimize powerconsumption. Low power consumption may increase battery life anddecrease the risk of tissue damage. Short pulse widths minimize chargein electrical stimulation, as explained by the charge-durationrelationship. Reduced charge minimizes the probability of inducingtissue damage. Theoretical studies indicate that short pulse durationsincrease the threshold difference between activation of differentdiameter nerve fibers (Gorman and Mortimer, 1983) and between activationof nerve fibers lying at different distances from the electrode (Grilland Mortimer, 1995). Empirically, short pulse widths may be found toincrease the dynamic range between clinical benefit and adverse sideeffects, also referred to as the therapeutic window. Rizzone et al.(2001) determined the pulse width/stimulus intensity relationships forreduction of wrist rigidity in patients with PD and for onset of sideeffects. As the pulse width is decreased, the stimulus intensityrequired to elicit a clinically significant improvement may increase,which may be explained by the strength-duration relationship. Thestimulus intensity causing side effects also may increase as the pulsewidth decreases, but the difference between the two amplitudes, the sizeof the therapeutic window, may increase as the pulse width decreases.Cumulatively, these results suggest that DBS devices may be programmedwith the shortest possible pulse duration, and that future generationstimulators may include lower ranges of pulse widths. Similarly, themost appropriate pulse width for light stimulation may be derived.Shorter pulses may be selected to decrease tissue damage. High frequencystimulation may require more power, and therefore decreases batterylife. DBS may be effective for reduction of tremor, akinesia, andrigidity at frequencies greater than 50 Hz but larger stimulusamplitudes may be required at low frequencies (Benabid et al. 1991;Limousin et al., 1995). Tremor suppression at the lowest current mayoccurr between 150 and 1000 Hz, and the lowest stimulus intensityrequired may be about 2 mA (Benabid et al., 1991). Above 1000 Hz, theefficiency of tremor suppression may decrease, presumably as a result ofneural refractoriness. The clinical effect of STN stimulation onakinesia and rigidity may be studied with similar results (Limousin etal., 1995). The stimulus amplitude required to activate neural elementsdepends on the spatial relationship between the electrode orlight-emitter and the nerve fiber (McNeal, 1976). As the distancebetween the active contact and the neural element is increased, thestimulus amplitude required to stimulate neural elements increasesnon-linearly. DBS studies have shown that the clinical benefits saturateabove a certain value.

Stimulation Patterns

In some embodiments it is preferable to use spatial patterns ofstimulation emanating from multiple stimulation sources. In one example,multiple stimulation contacts are inserted into neural tissue so thateach stimulation contact is in a different location. These locations mayspan different neural elements, such as slightly different locations ina brain nucleus, cortical area, or part of the spinal cord, peripheralnerve or muscle tissue. Then, the amount and timing of stimulation fromeach of the stimulation contracts may be individually adjusted so thatthe greatest stimulation of the tissue is achieved. The amount andtiming of stimulation from each of the stimulation contracts may also beindividually adjusted to minimize tissue damage with similar resultantstimulation or inhibition. The amount and timing of stimulation fromeach of the stimulation contracts may also be individually adjusted tomaximize the long-term effectiveness of stimulation over repeatedstimuli (eg decreasing habituation). In addition, spatiotemporalpatterns of stimulation to different sites may be controlled so thatdifferent spatial locations are stimulated at different times. This maybe important in producing precisely timed resultant patterns ofstimulation in the target tissue. For example, in muscle tissueindividual muscles may be stimulated a different times in a precisespatiotemporal pattern in order to produce a coordinated movement.Similarly, different neural elements may be stimulated in aspatiotemporal pattern to achieve or mimic desired patterns of neuralactivation or inhibition. These spatiotemporal patterns may be adjustedby adjusting the timing or intensity of stimulation at each componentstimulation site in order to optimize a desired response, such as asensation, movement, or decrease in symptoms in the subject. This mayalso be used to produce precisely controlled stimulation patterns inexperimental preparations that can be used to investigate the results ofthese patterns.

Stimulation Locations

In addition, the invention disclosed here may be used for thestimulation of the following neural structures, through the acute orchronic placement of a stimulator inside or adjacent the thesestructures. The light may be conducted to the location through a lightconductor, which may in turn be delivered through a canula, tube, orother method of delivery. Structures which may be stimulated include,but are not limited to: Spinal Cord, Subdural, Dorsal horn, Ventralhorn, Nerves, Cranial nerves #1-12, Peripheral nerves, Nerve roots.Stimulation locations include, but are not limited to those depicted inFIG. 6-8. Additional tissue targets and stimulation locations may befound in neuroanatomical texts.

Spinal Cord Stimulation

Using this invention the spinal cord 121 may be stimulated, replacing orsupplementing the results of electrical spinal cord stimulation. Thismay be used in indications where electrical stimulation of the spinalcord is indicated, such as in the treatment of chronic pain. Lightstimulation may be provided directly against neural tissue. If asuitable wavelength and stimulation parameters are available,stimulation may be made through intervening tissue.

Spinal cord stimulation is a method for stimulating or inhibiting neuralelements of the spinal cord, and thereby impacting their physiologicalfunctions. Using this invention spinal cord stimulation may be appliedusing light rather than or in addition to the prior approach usingelectrical stimulation.

Some clinical indications for spinal cord stimulation are:

Vascular pain: refractory angina andperipheral vascular diseases (PVD).Rachidian pain: failed back surgery syndrome(FBSS), degenerative low back-legpain (LBLP), spinal stenosis, nerve-root avulsion,incomplete spine lesion.Chronic regional pain syndromes (CRPS)type I and II.Neuropathic perineal pain:Urological diseases: interstitial cystitis, urge-incontinence.

Deep Brain Stimulation

This invention provides for deep brain stimulation using light as shownin FIG. 1. The target of deep brain stimulation may be a brain regioninternal to the brain B. The light for deep brain stimulation may beconveyed to the target tissue using a light conductor 22. Deep brainstimulation may use an implantable device 10.

Successful treatment with DBS depends on accurately placed electrodes orlight-emitters. Anatomical targeting involves determining where to placethe stimulator and where to direct the electric current, based on whichneural elements, cells or fibers, are targeted for excitation. The STN(sub thalamic nucleus) is a common target for the treatment ofParkinson's disease (PD), and targeting the STN for treatment of PDresults in clinically effective outcomes (Krause et al., 2001; Kumar etal., 1998; Limousin et al., 1995). The STN is a small nucleus,surrounded by several large fiber tracts, including the zona incerta(ZI) and the Fields of Forel (FF).

Light-emitters placed in the STN and the surrounding fiber tracts mayelicit similar clinical improvements (Hamel et al., 2003; Saint-Cyr etal., 2002; Voges et al., 2002; Yelnik et al., 2003). However, Saint-Cyret al. (2002) found that the best efficacy and fewest adverse sideeffects may occur most commonly when electrode contacts are located inthe anterior-dorsal STN and/or in the FF/ZI dorsally adjacent to it.Hamel et al. (2003) found that active contacts located at the borderbetween the STN and the area containing the ZI, FF, and STN projectionsmay require the least voltage to alleviate rigidity. Voges et al. (2002)found that, for a similar clinical improvement, contacts located in thefiber tracts may require less stimulation power (where Power ¼(Amplitude £ Pulse Width £ Frequency)2/Impedance) than those located inthe STN. Similarly, subthalamotomies that extended beyond the STN intothe FF/ZI may be more effective in the treatment of PD patients thanlesions that not extending beyond the STN (Patel et al., 2003). Fibertracts around the STN, the activity of which may be influenced by STNDBS, may play a role in mediating the motor effects of STN DBS (Voges etal., 2002). According to previous animal studies, neural elements up to5 mm from the cathode may be affected by stimulation using stimulusamplitudes (3 mA) that may be used in DBS (Ranck, 1975).

Therefore, stimulation in the STN may spread to the surrounding fibertracts (Voges et al., 2002). The globus pallidus (GP), or pallidum, isanother target for DBS treatment of PD. Stimulation of the GP, which iscomprised of the GPi and the external globus pallidus (GPe), may resultin different clinical effects with electrodes placed in the GPi or theGpe (Bejjani et al., 1997; Krack et al., 1998; Yelnik et al., 2000). DBSapplied to the GPe or the area between the putamen and GP (13 out 14contacts) may result in improved upper limb akinesia, whereasstimulation applied to the GPi (11 out of 12 contacts) may result inworsened upper limb akinesia. Contacts located at the border of the GPeand GPi may have mixed clinical effects. Rigidity may be improved forcontacts located throughout the GP, including the area between putamenand GP, in the GPe, in the area between the GPe and GPi, and in the GPi.

The invention disclosed here may be used to provide precisely locatedstimulation of deep brain structures. Light may be applied to deep brainstructures, such as brain nuclei, so that the desired target regions arestimulated by the light while other or surrounding regions arestimulated substantially less or not at all.

Stimulation of Brain or Cortical Tissue

In one embodiment this invention may be used to stimulate tissue of thecerebral cortex within the brain B, shown in FIG. 1. Many structures ofthe cerebral cortex are ‘mapped’ so that different points on thecortical surface correspond to different features, such as points invisual space, points on the body surface, or sound frequencies.Therefore, this invention provides for the creation of patterns ofactivity in cortical tissue through stimulation at selected intensitylevels at one or more points within cortical tissue. By applying astimulus pattern, this pattern may be used to mimic informationrepresented in electrical activity in brain tissue. For example, in theprimary visual cortex each point in the brain corresponds to a locationin visual space, and stimulation of each point may produce the perceptof an image at that point in visual space. Therefore, by stimulating apattern of points in the visual cortex of a subject, it is possible tomimic the representation by the subject's cortex of an image that isviewed by a subject.

This method also provides for the mapping of cortical or other braintissue. A light stimulus may be presented to a target location, and theresult may be observed, for example by determining whether the subjecthas a resultant perception, movement, or perturbation of a cognitivefunction such as language. Through repeating this procedure, it ispossible to form a map of the functions of different brain areas. Thismap may be used to avoid important brain areas during invasive surgery.

This invention provides that stimulation of target tissue, such as braintissue, may take place through multiple light-emitters being placed suchas to illuminate multiple points of target tissue.

In addition, this invention provides that stimulation of target tissuemay take place through moving the light spot produced by a single lightsource so that the light spot is scanned across the tissue. Theintensity of stimulation at each point in the tissue may be adjusted byrapidly scanning the light spot to a pattern of positions in the targettissue, and selecting the intensity, pulse width, or other parameters ofthe light so that each position may receive a different stimulationintensity. Stimulation of brain tissue may take place during exposure ofthe brain tissue, for example during surgery. This may be used todetermine the function of the target tissue being stimulated, forexample by observing the effects of stimulation, or having the subjectreport the effects of stimulation. Stimulation of brain tissue may alsotake place using implanted stimulation apparatus. This thereforeprovides for long term or chronic stimulation of brain or corticaltissue using light.

Stimulation of Brain Nuclei

In another embodiment, this invention may be used to stimulate one ormore brain nuclei. This may take place through placement of one or morelight emitters within or adjacent to the brain nucleus that will bestimulated.

Placement of Multiple Leads Via Cannula

In another embodiment, multiple light stimulation leads andlight-emitters may be positioned into different spatial locations withinthe target tissue. An example is presented in FIG. 9. In this example, aguide cannula 1010, for example an 18 gauge catheter, may be insertedinto target tissue region 1020, for example into a brain nucleus such asthe STN. Multiple light stimulation leads 1030 may be passed into thetarget tissue. These multiple leads may be passed into the target tissuethrough a cannula 1010 so that they enter the target tissue. It may bedesirable for the leads to enter different locations in the targettissue. The tensile properties of the leads, or of supporting elementsattached to them, may be designed to produce the effect of leadsentering the target structure in particular directions or achieving adesired final shape so that their tip reaches a targeted final location.For example, if each lead is designed to bend at a different circularradius and exit the cannula at a different angle, this will produce theeffect of the tip of each lead, and the light-emitter, reaching adifferent final target location with the target locations surroundingthe end of the cannula. This provides for the possibility that each leadwill stimulate a different location in the target tissue.

The level of stimulation through multiple leads may be individuallycontrolled so as to provide spatial control over the areas in targettissue that are stimulated. The level of stimulation through thelight-emitter at the end of each lead may be individually controlled.The result of stimulation of each individual light-emitter may beassessed in terms of the results of its stimulation. For example, instimulating tissue adjacent to a lead placed into the STN of aParkinson's patient, the results on a patient symptom such as tremor maybe evaluated when different stimulation parameters such as stimulusintensity or timing pattern are used with that lead. Then, once a levelof stimulation suitable to produce a desirable effect on patientsymptoms has been determined, this level or a fraction of this level maybe used for future stimulation through this lead in combination withstimulation through other leads using parameters determined in a similarfashion. In addition, some inappropriate leads 1040 may enter areas thatare not within the target tissue region. Through determining thatstimulation through a lead does not produce desired results, such as adecrease in tremor, or produces undesired results, such as patientmuscle twitches, it may be possible to determine that a lead is not in adesired target location and is therefore an inappropriate lead.Stimulation through inappropriate leads may thereafter be avoided. Inthis way, the stimulation of inappropriate leads that are not in thetarget region may be minimized. This method allows for the stimulationusing light of a spatial region within the target tissue. This methodalso allows for the avoidance of stimulation of undesirable regions.

Using a Light Conductor to Guide Placement

Light conductors 32, optical fibers or fiber optic bundles may be usedto guide the placement of stimulating light-emitters according to thisinvention as shown in FIG. 1. If an optical fiber's distal end isentered into the body of a subject, and the proximal end is connected toa light monitor or camera, then it is possible to use the optical fibersto make observations near the location of the distal end of the opticalfibers within the subject's body. Methods for viewing target tissuesthrough optical fibers have been well-developed in the field oflaparoscopy and are familiar to one skilled in the art. Methods ofplacement using catheters, guide wires or methods of visualization havebeen well described in the literature. These methods may be used in theplacement of light-emitters disclosed in this invention. In this way, itmay be possible to visualize the location of placement of a stimulatingelement such as a light-emitter being implanted into target tissue.Light for illumination of the target tissue may be provided through oneor more of the optical fibers by conveying light from the proximal endto the distal end, or light may be provided through a different source.

Experimental Stimulation of Isolated Neural Tissue

Tissue from a subject may be removed from the subject and stimulatedusing this invention. For example, a hippocampal slice preparation maybe removed from a rat or other experimental animal, and placed in anexperimental apparatus for maintaining its physiological functionaccording to methods familiar in the art, for example as described inSchmitz, D., Frerking, M. and Nicoll, R. A.: Synaptic activation ofpresynaptic kainate receptors on hippocampal mossy fiber synapses.Neuron 27:327-338 (2000). This may then be used as the target tissue forstimulation using the methods disclosed here. Whereas isolated neuraltissue is often stimulated with one or more stimulating electrodes, thisinvention provides for the stimulation of this tissue by one or morelight-emitters. Since a light-emitter does not generate a stimulusartifact, superior electrophysiological recording of resultant neuralactivity may be achieved. In addition, the present invention providesfor very precise spatial and temporal patterns to be generated, and theresulting physiological changes may be measured. For example, lightstimuli may be applied to a large number of locations in a section ofisolated neural tissue, such as a hippocampal slice, and the resultantneural activity may be measured. The isolated neural tissue used as atarget may also include cultured neurons, organotypic cultures, andother forms of maintained neural tissue. The stimulation used may bescanned to multiple points on the neural tissue to provide a precisespatial pattern of stimulation. For example, a single neuron may bestimulated through controlling stimulating light falling on differentpoints on the neuron's axons, dendrites, cell body, or on fibersincident on the neuron.

Mri Compatibility

This invention may be used to provide MRI compatible stimulation oftissue. This invention does not require implantation of metal lead wiresthat may not be MRI compatible. Light may be conveyed to thelight-emitter by MRI compatible optical fibers. In addition, theplacement of light-emitters may be guided by MRI, CT, or fluoroscopy. Inaddition, by placing an MRI receive coil adjacent to an implantedlight-emitter or a guide wire used in it's placement, and making MRImeasurement from this MRI receive coil using an MRI scanner, it ispossible to precisely visualize the location of implantation andsurrounding tissue.

Retinal Stimulation for Site Impairment

The methods described herein may be used to achieve stimulation of thevisual system. This stimulation may take place at the level of theretina, or at higher levels of the visual system including the opticnerve, optic tract, optic chiasm, lateral geniculate nucleus, primaryvisual cortex, or higher visual cortical areas. This may be used toachieve prosthetic effect, for example for the partial restoration ofsite in a visually impaired person. For example, by using pulsed laserexcitation one may activate neural tissue of the retina or optic nerve.This may be used in patients to produce vision restoration. Stimulationof the retina may be applied through the pupil of the eye by formationof an image on the retina. In cases where electrical stimulation of thevisual system has been employed, optical stimulation using thisinvention may be employed instead. For example, methods are disclosed inSachs and Gabel, ‘Retinal replacement—the development of microelectronicretinal prostheses—experience with subretinal implants’, 2004 for visualsystem prostheses. Rather than using electrical stimulation asdescribed, optical stimulation using this invention may be applied tothe corresponding points in the visual system. In one embodiment, aretinal prosthesis may be constructed using an array of multiplelight-emitters, each placed against a position on the retina. Thestimulation may be computer controlled, so that the exact position,time, and intensity of stimulation on the retina may be preciselycontrolled. In addition, a sequence of stimulation may be employed sothat different locations on the retina (or other neural structure) arestimulated in rapid succession.

Use in Virtual Retinal Display

In addition, stimulation may be accomplished by scanning a laserillumination spot to different points on the retina in rapid succession.Through modulating the laser pulse intensity at each location when it isreached, a different level of stimulation may be achieved at eachlocation. This may be used to achieve visual activation, for example inmacular degeneration, glaucoma, or other vision impairments. Thisprocess of scanning and modulation may also be used with a pulsed laser.The target point of each pulse may be scanned to different points on theretina, for example in a rectangular grid, and a laser pulse may beapplied at each point that corresponds to the intensity level of theimage being applied at that point. This is analogous to the analogprocess used in scanning a beam to different locations on a CRT monitorin order to form an image. In this case, however, stimulation of theretina or a visual system structure may take place through direct actionof light on target tissue, rather than through the process ofphototransduction through photopigments in photoreceptor cells. In thisway, direct stimulation of target tissue may be possible in cases wherephototransduction is not normally operational. The image formed may becaptured in real time using video or other equipment. This provides forvideo, or a rapid succession of images, to be applied to the targettissue as a spatial and temporal pattern of light intensity or lightpulses applied to each point on the target tissue. In addition, in orderto properly focus the laser pulse on the retina, a lens may be used, ora contact lens may be placed upon the eye. The conventional methods ofvirtual retinal display are described in, for example, Viirre E, PryorH, Nagata S, Furness T A “The virtual retinal display: a new technologyfor virtual reality and augmented vision in medicine”, Stud HealthTechnol Inform. 1998; 50:252-7 and in “Virtual Retinal Display (VRD)Technology”, presented inwww.cs.nps.navy.mil/people/faculty/capps/4473/projects/fiambolis/vrd/vrd_full.html.In these methods, the current invention discloses that laser lightpresented through a virtual retinal display may be used for directneuronal stimulation, in addition to phototransduction.

Disease Conditions and Indications

The disclosed invention may be used in the treatment of a variety ofdiseases involving the nervous system. In particular, in any case whereelectrical stimulation of the nervous system has been applied, opticalstimulation may be applied instead. Optical stimulation may also beapplied in addition. For example, deep brain stimulation of thesubthalamic nucleus for Parkinson's disease may be substituted usingoptical stimulation in a substantially similar location within thebrain. This may be accomplished by passing a fiber optic or fiber opticbundle into the corresponding location, and applying pulsed stimulationof the neural tissue. This stimulation may take place through astimulation window 23.

Any of a variety of conditions may be treated using this invention as areplacement for electrical or magnetic stimulation. In particular, in avariety of conditions where electrical stimulation of neural tissueusing a conventional electrode has been described, such as thosedescribed in appendix material cited here, optical stimulation of neuraltissue may be used as a replacement as disclosed here. These include,but are not limited to those depicted in FIG. 6-8.

Measurement of Activity

This invention may be used in conjunction with a variety of methods formeasuring physiological activity from a subject. Examples of measurementtechnologies include, but are not limited to, EEG, single neuronrecording, EMG, ECG, nerve potential recording, functional magneticresonance imaging (fMRI), PET, SPECT, magnetic resonance angiography(MRA), diffusion tensor imaging (DTI), ultrasound and doppler shiftultrasound. It is anticipated that future technologies may be developedthat also allow for the measurement of activity from localized regions,preferably in substantially real time. Once developed, thesetechnologies may also be used with the current invention. Thesemeasurement techniques may also be used in combination, and incombination with other measurement techniques such as EEG, EKG, neuronalrecording, local field potential recording, ultrasound, oximetry,peripheral pulsoximetry, near infrared spectroscopy, blood pressurerecording, impedence measurements, measurements of central or peripheralreflexes, measurements of blood gases or chemical composition,measurements of temperature, measurements of emitted radiation,measurements of absorbed radiation, spectrophotometric measurements,measurements of central and peripheral reflexes, and anatomical methodsincluding X-Ray/CT, ultrasound and others.

Any localized region within the brain, nervous system, or other parts ofthe body that is measured using physiological monitoring equipment asdescribed (or other physiological monitoring equipment that may bedevised) may be used as the target of this method. For example, ifmeasurement equipment is used for the monitoring of activity in aportion of the peripheral nervous system, such as a peripheral ganglion,then subjects may be stimulated for the regulation of activity of thatperipheral ganglion. In addition, the monitored point may be downstreamor affected by the region being stimulated. For example, if a nerve isstimulated, measurements may be made at a distal muscle or effectororgan that is innervated or activated by the nerve.

Example Experimental Preparation

One example of the use of this invention is to use the rat sciatic nervefor frog isolated nerve preparation, as described in U.S. Pat. No.6,921,413, for the target tissue which may serve as an example of itsapplication. One of ordinary skill in the art understands thedifferences in the surgical procedure necessary to expose the Ratsciatic nerve. Regarding the stimulation of the Rat sciatic nerve, awavelength of 4.4 micrometers, and energy of 4.7 mJ, a spot size of 619micrometers, and a pulse frequency of 2 Hz using the FEL may be used.Optical stimulation may also use an energy of 39 mJ, 1.78 mJ, and 2.39mJ.

The present invention described herein provides methods of stimulatingtarget tissue with optical energy. In other embodiments, the presentinvention provides a method of stimulating neural tissue by providing asource capable of generating an optical energy having a wavelength in arange of from 3 micrometers to 6 micrometers at an energy output in arange from 200 microjoules to 5 millijoules, providing a target neuraltissue, and focusing the optical energy on the target neural tissue sothat the target neural tissue propagates an electrical impulse. A sourceof optical energy that may be used is a free electron laser. Examples oftarget neural tissues include a mammalian nerve, a human nerve, asciatic nerve from a leopard frog in a model system.

The response of sciatic nerve to the optical energy stimulation may besensed using stainless steel needle electrodes that are placed under thesciatic nerve for compound nerve action potential recording.Additionally, the electrical response from the sciatic nerve may bemonitored by recording electrodes placed in the nerve downstream andinnervated hamstring muscle. If the sciatic nerve conducts an electricalimpulse, a tiny electrical signal may be detected from the nerve and amuch larger electrical signal can be detected from the muscle. Thesignals may be recorded using the MP100 system from Biopac Systems(Santa Barbara, Calif.) which is combined electrical stimulation andrecording unit. For comparison purposes, the nerve may be electricallystimulated using S44 Grass electrical stimulator from Grass Instruments,Quincy, Mass. At varying fluences, individual nerve fiber diameters andexcitation thresholds may vary by small increments.

The present invention, herein described, provides a method ofstimulating a nerve fiber by providing an optical source capable ofgenerating an optical energy having a wavelength in a range of from 1micrometers to 8 micrometers at an energy output in a range of 150microjoules to 5 millijoules, providing the target nerve fiber, andfocusing the optical energy on the target nerve fiber so that the targetnerve fiber is stimulated. The target nerve fiber can be a mammaliannerve fiber, a human nerve fiber, or a leopard frog sciatic nerve fiber.During focusing, the target nerve fiber receives the optical energy foran amount of time necessary to provide a stimulation effect. The opticalsource can be pulsed. When the optical source is pulsed, the pulse has arange of from 1 picosecond to 10 picosecond micropulse and from 1microsecond to 10 microsecond macropulse. Also, focusing of the opticalenergy occurs in an area in a range of 50 micrometers to 600micrometers.

In certain embodiments, the present invention provides a method ofexciting a target tissue comprising: (a) providing a laser to generate alaser beam having a wavelength in a range of from two micrometers tonine micrometers at a power output in a range of from 100 microjoules to5 millijoules, having an area in a range of 50 micrometers to 600micrometers, (b) providing a target tissue, (c) focusing the laser beamon the target tissue so that the target tissue conducts a nerve signal.It may be desired to pulse the light source. Although other pulse widthsand durations may be used, a pulse can have a range of from 1 picosecondto 10 picosecond micropulse and from 1 microsecond to 10 microsecondmacropulse.

The present invention also discloses a system used for stimulatingneural tissue without damaging the neural tissue. The present inventiondiscloses a method of stimulating neural tissue by providing an opticalsource to generate a beam of radiation having a wavelength whichapproximately corresponds to a valley for water absorption of a neuraltissue, providing the neural tissue, and directing the beam of radiationat the neural tissue to be stimulated. Also disclosed is a methodstimulating target tissue by providing a source capable of generating anoptical energy having a wavelength in a range of from 0.9 micrometers tosix micrometers at a fluence in a range of from 0.07 J/cm² to 25 J/cm²,providing a target neural tissue, and focusing the optical energy on thetarget neural tissue so that action potentials are propagated. Duringthis method, the source may be pulsed. Additionally, the target neuraltissue can be mammalian neural tissue, or human neural tissue.

The methods disclosed herein may not damage neural tissue. Neural tissuemay be irradiated at sub-ablative fluence, a wavelength of 4.5micrometers with a fluence of 0.84 J/cm². No discernible damage may becaused at this fluence. At fluence levels of approximately 0.84 J/cm²,levels that may induce clear potentials in a nerve, there may be nothermal damage as observed under light microscopy.

Energy is generally known to have three types of effects on tissue.While photothermal and photochemical effects on neural tissue have beenwidely studied, the third type of effect, photomechanical, appears toplay a minor role with regard to neural tissue. Thus, modifications tothe pulse parameters may be used to identify modifications to thephotothermal and photochemical responses by the neural tissues.

Spot size of the laser beam may be reduced in size. By doing so a smallportion of the target tissue may be selectively stimulated withoutdisturbing the other elements of the target tissue. By doing so, thismay be an effective way for an investigator to perform a functionalidentification of the target tissue. For exmaple, a researcher wouldhave the ability to map the different portions of a brain nucleus orcortical area to the specific muscular tissue they innervate, or thespecific symptom results that they produce. For a clinician, this willserve as a tool to selectively identify the points of damage within anerve or map subsections of the nerve.

Regulation of Targeted Brain Regions

One aspect of this invention relates to the selection of brain regions.As has been noted, the brain contains thousands of individually namedstructures with different functions and anatomical locations. There arealso hundreds of conditions that involve inappropriate functioning ofareas of the brain. As a result, there are many hundreds of thousands ofpotential treatment targets, each involving the inappropriatelyfunctioning area(s) of the brain for the particular condition.

As has been disclosed, this invention provides for the regulation ofdiscrete brain regions for use in the treatment of particular conditionsassociated with those conditions. Thus, by first selecting a region ofinterest based on a particular condition, various methods are providedfor the regulation of that region of interest and hence the particularcondition associated with it. For example, methods are provided thatallow one to measure activity of one or more regions of interestassociated with a particular condition; employ computer executable logicthat takes the measured brain activity and determines parameters for usein stimulation of tissue using this invention. It should be recognizedthat the other various methods according to the present invention can bedirected to any region of interest and thus can be applied to conditionsassociated with particular regions of interest.

A further aspect of the present invention relates to the localization ofparticular brain regions for use in the treatment of particularconditions. By knowing these brain regions, a device operator or subjectmay select and localize a region of interest.

FIG. 6-8 provide particular examples of brain regions that may be usedas regions of interest for stimulation and regulation, particularly asnoted in the columns labeled regions and coordinates. It is noted thatthe structures and coordinates shown in FIG. 6-8 should be understood toinclude either unilateral instances of these structures and positions ineither hemisphere, or bilateral instances of these structures includingboth hemispheres. In addition, an effective method for the stimulationof a given neural region may be the stimulation to regulate a namedanatomical target of one of the regions shown, rather than the locationitself, using the anatomical target as the region of interest forstimulation. Therefore, the named anatomical targets of the regionsdescribed in FIGS. 6-8 may be used in stimulation for the purposesdesignated, rather than or in addition to the locations themselves.

A device operator may also use the coordinates provided in FIG. 6-8 asthe center for a region of interest. These coordinates are presented instandard Talairach space. Therefore, before selection of a region ofinterest, these coordinates may be transformed into the coordinate frameof the subject being stimulated. The invention may then be used for themodulation of the selected region.

The regions designated in FIGS. 6-8 may be used as regions of interestfor any of the embodiments of the invention disclosed herein.Specifically, these regions may be used as the targets for brainstimulation. In addition, it will be understood by one skilled in theart that there is some variability in the location of structures acrosssubjects. The locations designated may be used as regions of interestfor any of the embodiments of the invention disclosed herein, as maylocations including these regions of interest, as may nearby locations,such as locations within 1, 2, 5, 10 cm from the described location.

Once the one or more regions of interest are identified and localizedfor the particular subject, and exemplar behaviors and/or stimuli may beidentified to use in stimulating the one or more region of interest forthe particular subject, stimulation of the one or more regions ofinterest can be performed according to the present invention.

Regulation of Targeted Brain Regions for Treatment of ParticularConditions

In addition to the large number of brain regions that may be used astargets for stimulation, such as those listed in FIG. 6-8, there arealso hundreds of conditions that involve inappropriate functioning ofareas of the brain.

By associating a given condition with a particular brain region, andthen by stimulating that particular brain region according to thepresent invention, treatment of the conditions can be achieved.Furthermore, some conditions relate to an injury or damage (such as froma stroke) to a given brain region. By knowing the location of the injuryor damage, localizing a region of interest relative to the injury ordamage, such as adjacent to the area of damaged tissue, stimulation ofthe regions can be performed. For example, in one embodiment, a methodis provided according to the present invention comprising taking asubject having a condition, identifying one or more regions of interestfor the subject where the treatment of those one or more regions wouldbenefit the subject regarding the condition; and stimulating the one ormore regions according to a method according to the present invention.Examples of particular conditions and associated regions of interest areprovided in FIG. 6-8.

FIGS. 6-8 present combinations of brain regions of interest, andparticular conditions for which those regions of interest may beappropriately used in stimulation. When a subject has been identifiedand screen who has a particular condition, one or more regions ofinterest may be selected from FIGS. 6-8 that is appropriate to thecondition of the subject, and stimulation of the one or more regions ofinterest may be performed according to the present invention. It will benoted that some regions of interest are related to more than onecondition, for instance, the nucleus basalis provides cholinergicinnervation of the cerebral cortex, so it is involved in normal learningand plasticity, and it is also involved in the loss of memory associatedwith the decreased cholinergic functioning found in Alzheimer's disease.Similarly, the substantia nigra is a primary source of dopaminergicmodulation, which has been repeatedly shown over many decades to beinvolved in both Parkinson's disease and schizophrenia. As anotherexample, stimulation of the anterior cingulated cortex, and/or therostral anterior cingulate cortex, may be used in the treatment ofchronic pain.

As another example, subjects with Alzheimer's disease have decreasedactivity in the nucleus basalis of Meynert, due in part to neuronaldegeneration. This decrease in activity in nucleus basalis is understoodin the art to lead to a decrease in cholinergic activation of thecerebral cortex, with resulting memory and cognitive impairments. Onceagain, prior art has described electrical stimulation of the nucleusbasalis as a means of overcoming certain effects of Alzheimer's disease.In one example of using the present invention, these subjects withAlzheimer's disease may be treated through stimulation that allowsincrease in the activity in the nucleus basalis. This may lead thenucleus basalis to release acetyl choline onto neurons in the cortex ata higher level than the diminished level found in the disease state.

As another example, subjects with Depression have decreased activationboth in the serotonergic nuclei, and in certain cortical zones includingfrontal lobe regions. Subjects with depression and other psychologicaldisorders such as social phobia may be treated by stimulation ofserotonergic nuclei. These nuclei may release serotonin and increase itslevel to higher than the diminished level found in the disease state, aswell as increase the activity level of certain target regions ofserotonergic modulation, such as frontal cortical regions. Depressionmay also be address through stimulation of the subgenual cingulate usingmethods provided here.

As another example, subjects with chronic pain may be treated throughthe control of certain antinociceptive regions of the brain, as providedfor in FIG. 6-8. Activation of these regions, which may include theperiaqeuductal gray, nucleus raphe magnus, insula, cingulate cortex,somatosensory cortex, medial thalamus, and dorsal horn of the spinalcord, may lead to a decrease in experienced pain. Subjects may bestimulated using one or more of these regions as a target tissue.

As another example, subjects with epilepsy have areas of the brain whereexcessive activation leads to seizures. This method provides forstimulation within or adjacent to epileptic tissue in order to disruptor prevent an epileptic seizure. Seizure activity may be monitoredthrough measurement of brain electrical activity, computations may bemade to determine the presence or likely onset of a seizure, and thismethod may be used to produce stimuli to the epileptic tissue, toadjacent tissue, or to connected tissue that will block, prevent, ordiminish the seizure.

Regulation of Targeted Brain Regions for Neuromodulatory Effects

There are a large variety of areas in the brain that serve the primaryrole of releasing neuromodulatory agents, such as opioids,neuropeptides, acetylcholine, dopamine, norepinephrine, serotonin andother biologic amines, and others. Many of these compounds are thecompounds mimicked by exogenously administered pharmacologic agents. Thestimulation of particular brain regions may be used to stimulate therelease of particular neuromodulatory agents that are released whenthose regions become active. For example, in one embodiment, a method isprovided according to the present invention comprising: identifying oneor more regions of interest that release neuromodulatory agents for asubject; and stimulating the one or more regions according to a methodaccording to the present invention such that an amount ofneuromodulatory agents released by the regions of interest is altered,preferably increased. Examples of particular release neuromodulatoryagent releasing regions of interest are provided in FIGS. 6-8.

By associating a given condition with a neuromodulator, and then bystimulating that particular brain region according to the presentinvention, the release of that neuromodulator can be achieved. FIGS. 6-8presents combinations of brain regions of interest, and particularneuromodulators for which those regions of interest may be appropriatelyused in stimulation. When a subject has been identified and screened whowould be expected to benefit from the adminitration of a particularneuromodulatory substance, or from pharmacologic agents designed tomimic that neuromodulatory substance, one or more regions of interestmay be selected from FIGS. 6-8 or from other brain regions that areappropriate to that neuromodulatory substance, and stimulation of theone or more regions of interest may be performed according to thepresent invention. The release of the neuromodulatory substance may thenbe monitored using methods for monitoring peripheral or central levelsof a neuromodulator that are described in the literature, or usingbehavioral or symptom meausres. Scanning methods such as PET may be usedto measure the level of central neuromodulators released.

It is noted that sub-regions of neuromodulatory centers may also becontrolled according to the present invention so that not all targetseven of a single neuromodulatory center receive the same level ofincreased activation. This may allow a degree of specificity of thegeneration of internal release that may be even greater. It may also bepossible to control multiple neuromodulatory areas together to producecombined effects.

As an example, subjects that would benefit from the use of serotonergicdrugs such as citalopram, fluoxetine, fluvoxamine, paroxetine andsertraline, may be stimulated to activate brain regions thatendogenously release serotonin, such as those described in FIGS. 6-8.Specifically, if a subject is stimulated to activate the raphe nucleus,this may lead to the release of serotonin.

Regulation of Targeted Brain Regions for Plasticity and Learning

The present invention may also be used to enhance neuronal plasticityand learning. For example, in one embodiment, a method is providedaccording to the present invention comprising: identifying one or moreregions of interest associated with neuronal plasticity and learning fora subject; and stimulating the one or more regions according to a methodaccording to the present invention such that neuronal plasticity andlearning for the subject is improved. Examples of particular neuronalplasticity and learning regions of interest are provided in FIGS. 6-8.

Several regions in the brain are known to be involved in controllingplasticity generally, including for example, those listed in FIGS. 6-8.Such regions may be selected and localized, for example the selectionand localization may be carried out as described in section 4, and asubject is selected. The selection of subjects is as provided for insection 2, selecting subjects that will benefit from enhanced plasticityor learning of a particular task, or particular knowledge. Additionalmaterial may also be presented to the subject to guide the subject'slearning. The invention may then be used for the stimulation of theregion designated in FIGS. 6-8. The invention may also be used tostimulate an additional region of interest during the modulation of aregion involved in enhanced plasticity, for the purpose of improving thestimulation and modulation of that additional region. By stimulatingmultiple regions a synergistic effect may be achieved. In addition, byrepeated stimulation of multiple regions of the brain or targets, theactivation of those to regions may become more greatly coupled throughsynaptic plasticity.

The regions associated with plasticity and learning have been shown tolead to increases in plasticity and learning when they are activated. Amethod is provided for enhancing plasticity and learning by increasing alevel of activity in one or more of the regions designated in FIGS. 6-8as being involved in plasticity and learning. This region may beselected as a region of interest for stimulation. This may constituteincreasing the activity of one or more regions involved in plasticity orlearning.

Use in Combination with Other Interventions

The methods described in this invention may be used in combination witha number of different additional methods, as described here.

Use in Combination with Pharmacology

It is recognized that the various methods according to the presentinvention may be performed in combination with pharmacologicintervention which may make such methods more effective.

Producing Brain Activation Similar to that Produced by PharmacologicAgents

Stimulation may be used to replicate the activity provided by apharmacologic agent. This would allow discontinuation of the drug use orreduction of the drug dosage. According to this variation, brainactivity in selected regions is measured with and without thepharmacologic agent, and regions of interest are defined as regions witha selective difference in activation between these two conditions. Then,those identified regions of interest are targeted to be stimulatedaccording to the present invention. This may also take place incombination with the provision of the pharmacologic agent, which mayincrease the efficacy of the pharmacologic agent, or decrease thenecessary dose.

In the example case of Parkinson's disease, any pharmacologic agent thatameliorates Parkinson's disease symptoms may be used. Particularexamples include, but are not limited to: L-dopa, pergolide,bromocryptine, promipexole and ropinirole. When a patient has beenadministered one of these agents and shows improved symptoms, brainactivity may be measured in all or part of the brain. This measurementmay take place using brain imaging such as fMRI or PET. This activitymay be compared with activity in the absence of the agents, or whensymptoms are worsened. The activity pattern measured during successfultreatment with one of these agents, or the difference between thepattern measured during successful treatment and without successfultreatment, may be used as a target activity pattern for stimulation.

Use in Combination with Device or Pharmacologic Testing

It is envisioned that the present invention may also be used todetermine the likely long-term success outcome of a pharmacologictreatment, or to set appropriate dosage for that treatment, or to testthe effectiveness of stimulation.

It is noted in regard to this section that the subject used here may notbe human but rather may be another animal, such as a mouse, rabbit, cat,dog, monkey, sheep, pig, or cow that is to be used in testing. Becausesuch animals do not have the cognitive ability of humans to receive andprocess instructions, it is recognized that the stimuli or instructionsfor behavior used will necessarily be limited to those stimuli orinstructions for behavior that the animal can be effectively asked toperform or which the animal can be made to perform. For example, thestimulus may be an external stimulus such as a sound, a smell, a brightlight, or a nociceptive stimulus, that is applied to the animal.

In order to test a pharmacologic agent, the methods provided here may beused to stimulate a target tissue in the presence of differentconcentrations of the pharmacologic agent, or in the absence of thepharmacologic agent, and the physiological response may be compared. Forexample, in a hippocampal slice preparation the methods disclosed heremay be used to stimulate fibers synapsing onto a group of neurons whoseactivation is measured electrically, including glutamatergic synapsingfibers. The electrical potential in a target cell or population of cellsmay be recorded that results from light stimulation of the fibers usingthis method. Then, a drug such as a potential glutamate antagonist maybe applied, for example in fluid 35 through catheter 34. The electricalpotential may be compared in the presence and absence of the drug todetermine the drugs effect. Similarly, methods may be used to monitorthe effect of a drug on a physiological response induced using lightstimulation in vivo.

Localization of Neuronal Function, Especially for Neurosurgery

The present invention may also be used to localize within the brain thecorrelates of certain psychological or neurological functions. Forexample, through stimulation it may be possible to determine the areasthat underlie particular psychological or neurologic functions. If thephysiological criteria selected are stimulation correlated with aparticular behavioral outcome, then the brain regions engaged duringstimulation and performance of this task are determined. This can beused as a method for determining where areas are located. This may beuseful in neurosurgery, such as for the sparing of regions or hemisphereinvolved in language, and regions involved in motor control.

Three Dimensional Light Patterns

Light stimuli may be shaped to produce 3 dimensional patterns. This maybe accomplished through lenses, multiple beams which converge on a givenlocation, or holography. One or more lenses may be used to focus lightupon a target location, thereby achieving specificity of stimulationlocation. In the case of holography, a hologram may be used thatproduces laser stimulation at a 3 dimensional array of locations,defined by the hologram. For example, if a hologram is created thatcorresponds to an image of a neural structure, and this hologram is usedwith applied laser light, this allows the laser light to produce thegreatest activation in the region of the intended neural structure.

Types of Light Sources

In addition to the types of sources already described, light sourcesused in combination with this invention may include, but are not limitedto, those summarized in FIG. 10.

Nerve Cuff Light-Emitter

In one embodiment, light-emitters may be fashioned to be positionedaround a nerve fiber or nerve bundle to form a cuff, as shown in FIG.11. This method may be adapted from nerve cuff electrical stimulationmethods, such as provided in U.S. Pat. No. 5,824,027. Electrodes usedfor nerve stimulation may be replaced by light emitters for nervestimulation. Similar to the use of nerve cuffs using electricalstimulation, the current invention provides for a light-emittersurrounding an element of tissue so as to stimulate the tissue frommultiple angles. The light-emitter may provide light at multiplelocations adjacent to the tissue being stimulated, and at multiplepoints along the length of the tissue, e.g. multiple points along anerve. In one embodiment, separate elements of the target tissue such asseparate groups of neurons in a peripheral nerve or brain nucleus may beindividually controlled through individually controlling multiplestimulating light-emitters, each adjacent to an element of the targettissue.

FIGS. 11A and 11B illustrate a nerve cuff 1110 according to a furtheralternative embodiment of the invention. Nerve cuff 1110 comprises aself-curling sheet 1111 biased to curl upon itself around an axis 1115to form an annular nerve cuff having a bore. A nerve can be insertedthrough bore by unrolling sheet 1111 and then permitting sheet 1111 tocurl around a nerve in a controlled manner. Nerve cuffs of this generaltype are described in Naples et al., U.S. Pat. No. 4,602,604. Aplurality of rounded ridges 1130 extend along sheet 1111 in a generallylongitudinal direction.

When nerve cuff 1110 is in its curled up configuration, as shown in FIG.11B, ridges 1130 project into bore. One or more light emitters 1120suitable for nerve stimulation and/or recording may be provided on sheet1111 between ridges 1130. In the alternative, fluid conduction means,such as tubes, may be provided to conduct fluids into or out of bore.

Vagal Nerve Stimulation

In one embodiment, light stimulation may be used to stimulate the vagusnerve, replacing electrical stimulation. Vagal nerve stimulation may beused as a replacement for electrical stimulation in all known andpotential future uses for vagal nerve stimulation, including Epilepsy,Depression. Vagal nerve stimulation is described in Schachter S C.“Vagus nerve stimulation: current status and clinical applications”Expert Opin Investig Drugs. 1997 October; 6(10):1327-35 and referencescited therein.

Tissue Measurement

The light conductor provided in this invention may be used for theoptical measurement of tissue activity. For example, blood oxygenationwithin the subject may be measured through measurements of the spectrumof light observed through the light conductor. Nerve or neuronactivation may also be measured using optical measurements through alight conductor.

Characterization of Brain Regions

An additional example of this invention relates to the characterizationof brain regions of unknown or only partially known function. Throughthe use of this invention, it is possible to characterize thefunctioning of a localized brain region of interest. IR this example, abrain region to be characterized is selected as a region of interest. Aprocedure is laid out for the stimulation of brain regions of interest.This knowledge of the characterization of a brain region may be used fora variety of purposes. For example, this new knowledge may be used todesign treatments involving the characterized brain region of interest.These treatments may include pharmacological treatments, surgicaltreatments, electrical stimulation treatments, or other treatments. Theknowledge of the characterization of a brain region may be used fordiagnostic purposes as well. For instance, if it has been determinedthat a brain region of interest is implicated in a condition, such as adisease, then using the stimuli or behaviors determined to engage thatbrain region may be used as a diagnostic for whether a subject has thatcondition, and the extent or severity of the condition. These stimuli orbehaviors determined to engage the brain region may also be used inconjunction with a pharmacologic treatment as a means for determiningthe effect of the pharmacologic treatment on the activation observed inthe brain region of interest in the presence and absence of thepharmacologic treatment. This may be used as a means for assessing thepharmacologic treatment.

1. A system for stimulating target tissue comprising: a light source forproviding stimulation pulses; an implantable light conducting leadcoupled to said light source adapted for stimulation of a predeterminedsite in a subject.
 2. The system, as claimed in claim 1, wherein saidlight conducting lead is an optical fiber.
 3. The system, as claimed inclaim 1, wherein said light source is a laser.
 4. The system, as claimedin claim 2, wherein said light source is implantable.
 5. A method oftreating a disorder comprising: implanting at least one light-emittercoupled to a light source such that it is in communication with at leastone predetermined site in the nervous system of a body; stimulating saidat least one predetermined site in said nervous system of said bodyusing said at least one light-emitter.
 6. The method of claimed in claim5, wherein said disorder is Parkinson's disease, Alzheimer's disease,depression, or epilepsy.
 7. The method of claim 5 further comprising thestep of regulating at least one parameter of said step of stimulating,said at least one parameter being selected from the group consisting ofpulse width, pulse frequency, and pulse amplitude.
 8. A method fortreating a disorder in a patient comprising the steps of: surgicallyimplanting a light-emitter into a brain of a patient wherein said lightemitter is coupled to a light source and a signal generator operatingsaid light source; and operating said signal generator to stimulate apredetermined treatment site in said brain.